This invention relates to novel radiosensitizing compounds, and in particular, to substituted taxanes containing radiosensitizing moieties, their pharmaceutical preparations, and methods of using this new class of highly potent radiosensitizers of tumor cells.
In the United States alone, over a half million patients undergo radiation therapy each year as a part of their battle against cancer. To date, however, radiation therapy has produced only limited success as a cancer treatment. Understandably, therefore, a major effort has been underway for a number of years to develop means to improve the efficacy of such radiotherapy techniques.
It is widely believed that the presence of radioresistant, hypoxic (poorly oxygenated) cells in tumors constitutes a significant factor in causing local failure in conventional cancer radiotherapy. For example, it was reported by Gatenby et al., Int. J. Radiat. Oncol. Biol. Phys. 14: 831-833 (1988), that for head and neck tumors, the hypoxic cell volume is inversely correlated with tumor radiosensitivity. Other reports confirm this conclusion for a variety of types of tumors and suggest that the presence of a concentration of as little as 2-3% hypoxic cells in a tumor may double the radiation dose required for tumor control.
Various solutions have been proposed to overcome the problem of hypoxia, including carrying out radiation treatments in high pressure oxygen chambers and the substitution of “fast neutron” or π meson radiation in place of X-rays. However, these techniques are not wholly satisfactory for a number of reasons, including the great expense and difficulty frequently associated with such procedures.
One promising field of investigation for dealing with radioresistant hypoxic tumor cells has been the use of “radiosensitizing” compounds which selectively increase the sensitivity of hypoxic cells to radiation. This specificity to hypoxic cells is also valuable because a significant percentage of solid tumors are characterized by such cells while most normal tissue is not. Thus, treatment with such compounds serves to enhance the impact of radiation on tumor cells while having little effect on the impact of radiation on healthy cell tissue. A number of heterocyclic, electron-affinic compounds, and in particular, those with oxidized nitrogen moieties, have been successfully used for the purpose of radiosensitizing hypoxic tumor cells. Specifically, the discovery that the nitroimidazoles, metronidazole (metro) and misonidazole (miso), sensitize hypoxic cells to radiation provided initial optimism for a breakthrough solution to the problem of tumor hypoxia. Unfortunately, however, both agents have proven to be highly toxic at therapeutic levels.
The possibility of using chemotherapeutic agents to selectively enhance radiation response in tumors has also been proposed. In addition to its use a chemotherapeutic agent, taxol, for example, has been investigated in vitro and in vivo as a potential radiosensitizing drug. See, Tishler et al., Radiation Oncology Biol. Phys., 22:613-617 (1992); Tishler et al., Cancer Research, 52:3495-3497 (1992); Steren, et al., Gynecologic Oncology, 48:252-258 (1993); Steren, et al., Gynecologic Oncology, 50:89-93 (1993); Choy et al., Cancer, 71:3774-3778 (1993); Milas et al., Cancer Research, 54:3506-3510 (1994); and Joschko et al., Proceedings of the American Association for Cancer Research, 35:647 (1994). Although the reported data suggests that taxol is an effective radiosensitizer, recent data from our laboratory leads us to question whether the reported data has been misinterpreted. In any event, a need continues to exist for compounds which possess antitumor activity and which are more potent radiosensitizers and thus, can be administered at lower doses to reduce toxic side effects.